Leukocytes NSAIDs

Pfizer s tenidap (CP-66,248) (157), another enolic compound, was also more potent (500-fold) toward CO over 5-LO inhibition in human ISN (0.032 /iM and 18 /iM, respectively) [379-381]. Efficacy in rheumatoid arthritis clinical trials has been reported [380,382] in patients, serum levels of acute phase proteins and synovial fluid levels of IL-1 were reduced by tenidap, in contrast to the lack of this effect with NSAIDs. Besides CO/5-LO inhibition, a variety of in vitro activities have been reported, including a number of effects on monocyte functions and differentiation [379], inhibition of neutrophil degranulation [382], inhibition of the activation of neutrophil collagenase [383], inhibition of leukocyte-endothelial cell adhesion [384], and inhibition of LTB4-induced neutrophil chemotaxis [385]. Al-... 

One of the first compounds reported to inhibit 5-LO was the NSAID benox-aprofen (167) (reviewed in [405]). This drug (marketed by Lilly as Oraflex ) was effective in rheumatoid arthritis, but was withdrawn because of phototoxicity, liver toxicity and reports of drug-related deaths [406]. The typical NSAID anti-inflammatory profile of this compound was remarkable for its very weak seminal vesicle CO activity [407]. Additional in vivo activities were found for benoxaprofen which were not shared by other NSAIDs, particularly inhibition of leukocyte influx in the carrageenan sponge, carrageenan pleurisy, and rat Arthus pleurisy models monocytes were affected more than neutrophils [408-411]. More recently, benoxaprofen was reported to inhibit the adhesion of monocytes to endothelium [412]. 

NSAID treatment alone. They may be used concurrently with NS AIDS. It mostly takes 1-3 month for their anti-inflammatory action to become apparent. The pharmacodynamics of these antimalarials in RA is uncertain. Possible mechanisms include decreased leukocyte chemotaxis, stabilization of lysosomal membranes, inhibition of DNA and RNA synthesis and trapping of free radicals. 

NSAIDs exert analgesic, antipyretic, anti-inflammatory and related effects. During pain, fever and inflammation the arachi-donic acid is liberated from the phospholipid fraction of the cell membrane which is then converted to prostaglandins (PCs) via cyclooxygenase pathway (both COX-1 COX-2). COX-1 is present in kidney, stomach and blood vessels and COX-2 is present in activated leukocytes and other inflammatory cells. 

There is some evidence that carprofen is an effective NSAID when used in horses at recommended doses (Table 14.1). For example, using an in vivo model of non-immune acute inflammation, carprofen was found to decrease swelling significantly and to decrease the production of TXB2 moderately (Lees et al 1994). As expected, there was no effect on the leukocyte numbers in the exudates but, somewhat surprisingly, there was not a correlation between the antiedematous effects of carprofen and its concentration in plasma or exudate. In this study, the authors concluded that... 

A number of experimental studies have been performed looking at the gastroduodenal damaging effects of non-steroidal antiinflammatory drugs (NSAID) such as indomethacin [193]. In these studies, orally administered 5-methoxyflavone inhibited indomethacin-induced leukocyte adherence to mesenteric venules, suggesting a role of inhibition of leukocyte adherence in gastroprotective activity of this flavonic compound. 

Figure 36-2. Sites of action of some anti-inflammatory drugs in a gouty joint. Synoviocytes damaged by uric acid crystals release prostaglandins (PGs), interleukins (ILs), and other mediators of inflammation Polymorphonuclear leukocytes (PMNs). macrophages, and other inflammatory cells enter the joint and also release inflammatory substances, including leukotrienes (eg, LTB ), that attract additional inflammatory cells. Colchicine acts on microtubules in the inflammatory cells. NSAIDs act on cyclooxygenase-2 in all of the cells of the joint.

The inhibition of cyclooxygenase by NSAID occurs at concentrations (0.01-10 pg/ml) comparable to their therapeutic levels. On the contrary, much higher concentrations of these drugs are required to regulate other processes which might underly their anti-inflammatory effect, such as uncoupling of oxidative phosphorylation or inhibition of leukocyte phagocytosis. A remarkable parallelism has been... 

Proceeding from the observation that aspirin specifically triggers the release of 15-hydroxyeicosatetraenoic acid (15-HETE) (Fig. 9.3 Sect. 3.2.5.2 and Fig. 3.8) from epithelial cells of nasal polyps and peripheral blood leukocytes from patients with aspirin-induced asthma/rhinosinusitis, 15-HETE generation was utilized as a test for the identification of aspirin-sensitive patients. Stimulation in vitro of peripheral blood leukocytes with 200 pM of aspirin resulted in a mean increase of over 400 % in 15-HETE generation but only small to insignificant responses were seen in aspirin-tolerant asthmatic and control subjects. Sensitivity of the test was 83 % and specificity 82 % positive and negative predictive values were 0.79 and 0.86, respectively. The NSAID COX-1 inhibitor naproxen also triggered 15-HETE release but COX-2-selective NSAIDs did not. 

HLA human leukocyte antigen HuCD4 human cluster differentiation 4 HuTNF human tumour necrosis factor MHC major histocompatibility complex NSAID non-steroidal anti-inflammatory drug RA rheumatoid arthritis... 

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